Project summary HIV-exposed uninfected (HEU) children in sub-Saharan Africa have poorer health outcomes in the first 2 years of life than HIV-unexposed uninfected (HUU) children, with higher mortality, more illness episodes, poorer growth and impaired cognitive development. However, it remains uncertain whether these disparities persist as children enter school, and what the underlying causes are in early life. Impairments in health, growth and neurodevelopment are likely multifactorial, including both HIV-specific risk factors such as exposure to maternal viremia and antiretroviral drugs, and universal risk factors such as poverty, low birth weight and maternal depression. This proposal leverages an existing cohort of HEU and HUU children in rural Zimbabwe, who were well characterized from early pregnancy to 2 years of age, and are now turning 7 years old. The goal of this proposal is, first, to understand whether health differences persist at school-age, by undertaking holistic assessments of the growth, physical and cognitive function of HEU and HUU children in mid-childhood and, second, to identify the network of underlying causes in early life, by leveraging the rich dataset of `exposome' measurements between early pregnancy and 2 years of age. In the first phase of this grant (R61), a cohort of 900 children, previously followed longitudinally in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe, will be identified by a network of Village Health Workers (VHW) and re-enrolled at 7 years of age. All HEU children who participated in SHINE from an entire rural district will be identified (N=300), and for each enrolled HEU child, 2 HUU children matched on age, sex and cluster will be selected (N=600). HIV exposure and infection status, social circumstances, major adversities and medical history of mother-child pairs will be updated, and each child will be linked to existing meta-data on biological, social and environmental exposures from pregnancy to 2 years of age. A holistic baseline assessment will compare growth, physical and cognitive function between HEU and HUU children, and the cohort will begin monthly prospective health surveillance by VHW to identify acute illness, clinic visits and hospitalization episodes in real-time. At the end of the R61 phase, disparities in school-age growth, physical and cognitive function between HEU and HUU children will have been characterized, and the early-life factors associated with these differences identified. In the second phase (R33), monthly prospective health surveillance by VHW will continue, and an annual assessment of growth, physical and cognitive function (with storage of biological specimens) will be undertaken, to identify longitudinal disparities between HEU and HUU children at ages 9, 10 and 11 years, and the early-life exposures associated with these outcomes. A subgroup of 300 children (150 HEU and 150 HUU) will undergo deep phenotyping of cognitive function, mental health, body composition, metabolic health, inflammation and chronic comorbidities using a range of cutting- edge techniques, to provide detailed insights into the functional capacity of HEU children in mid-childhood.